BACKGROUND The etiology and pathogenesis of chronic inflammatory arthropathies, such as rheumatoid arthritis (RA), is not well understood. Infectious triggers have long been suspected for some forms of arthritis, and have been identified in the context of so called reactive arthritis (ReA). In the case of RA, a number of pathogens have been suspected, and in some studies, clinical and molecular evidence of association has been demonstrated for specific organisms. Studies in a wide spectrum of populations have failed to confirm a consistent association with a single pathogen. This has led to the hypothesis that multiple pathogens can potentially serve as either initiators or amplifiers of the inflammatory process which is centered primarily in the synovial membrane.At initial presentation, RA, spondylarthropathies, and other undifferentiated arthropathies frequently overlap in their clinical manifestations. This poses a significant challenge for clinicians who attempt to identify prognostic subsets in these disorders, to which appropriate therapeutic strategies can be applied. To date, some insights have been gained in the assessment of prognosis in RA. A number of clinical, serologic, and immunogenetic features have been shown to be associated with poor outcome. In the case of spondylarthropathies, there is less known about determining prognosisIt is clear that the chronic inflammatory process centered in the synovial membrane is the most important determinant of articular damage in chronic arthropathies. Through a complex interaction between cellular recruitment, proliferation, and activation, a pannus of inflamed, proliferative, tumor-like synovium invades and destroys the adjacent bone and cartilage, resulting ultimately, although not predictably, in functional loss.Thus, one of the major challenges currently facing clinicians who diagnose and treat arthritis patients is the identification of prognostic and, if possible, etiologic subsets early in the disease process.THE NIH EARLY SYNOVITIS COHORT In 1994 a cohort of patients with early synovitis was established to define pathogenetic mechanisms, identify prognostic factors, as well as look for infectious agents which may be involved in the etiology and/or pathogenesis of arthritis.Patients with synovitis of one or more peripheral joints of less than 12 months duration have been recruited to this protocol. At entry the patients undergo a thorough clinical evaluation, along with a detailed hematological, biochemical, serological, radiographic, and immunogenetic assessment. All patients undergo a closed synovial biopsy at this initial visit. Synovial fluid and tissue are analyzed for the presence of specific genes from pathogens such as chlamydia trachomatis, using PCR and in situ hybridization. The synovial membranes are assessed histopathologically and immunohistologically. The patients are then reevaluated clinically at 6 weeks, 6 months, and 1 year. In 1998, a new protocol, 98-AR-0150, was established to define the outcome of the synovitis after the initial number of years of disease. Patients enrolled in the original protocol, 94-AR-0194, are brought back 2-5 years into their disease, and undergo clinical, laboratory, and radiographic evaluation, as well as repeat synovial biopsy, if their synovitis persists. The data generated from this visit is then correlated with data generated during their initial year of evaluation. RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVESA number of initiatives and studies centered around this cohort have either come to fruition over the past year, or are ongoing. These include the following: 1. A total of over 300 patients have been enrolled in the study. Approximately 50 have undergone an evaluation under the extended follow up protocol, 98-AR-0150. Analysis of the cohort reveals that 45% of the patients fulfill ACR criteria for RA at presentation, while 20% fulfill the European Spondylarthropathy Study Group (ESSG) criteria for spondylarthropathy. The remaining 35% do not satisfy either of these criteria sets, and are thus deemed to be undifferentiated arthropathies. 2. HLA data generated from the cohort suggests that a number of MHC class I and II alleles are overrepresented in the cohort, and are associated with specific clinical features(El-Gabalawy HS, et al, Arthritis and Rheumatism, 42:1696,1999). In collaboration with Dr Ron Wilders lab, the work is being extended to evaluate a number of other genes within, and outside,the MHC which may be part of large arthritogenic haplotypes.3. In collaboration with a number of centers around the world, a spectrum of novel, RA associated autoantibodies have been studied in this cohort. The data suggests that specific autoantibodies, in combination with immunogenetic data, can be used to effectively define diagnostic and prognostic subsets in RA (Goldbach-Mansky R, et al, submitted).4. Extensive studies continue to be performed around the area of microbial triggers of early arthritis. The focus has been of 3 pathogens; chlamydia trachomatis, parvovirus B19, and proteus mirabilis. Many of the studies are nearing completion and will be submitted for publication over upcoming 12 months.5. The expression and activity of matrix metalloproteinases, particularly the gelatinases, has been explored in the early synovial tissue samples, and appear to correlate with early erosion formation (Goldbach-Mansky R, el al, submitted) 6. In collaboration with investigators at UCSD, embryonic gene expression of the wnt and frizzled family in RA synovial tissue continues to be evaluated and compared to other arthropathies, and normal synovial tissue. NEW INITIATIVES4. The application of sensitive imaging techniques such as MRI and PET to the evaluation of the synovium, articular cartilage, and subchondral bone is currently being undertaken in new protocols. In impact of biologic therapies on the synovial and articular lesions will examined using these techniques. SIGNIFICANCEA unique cohort of early synovitis patients are being recruited to the NIH. The strengths of this initiative relate to the heterogeneity of the cohort, allowing it to be representative of what clinicians encounter in routine clinical practice. The acquisition of synovial tissue samples from the entire cohort allows the testing of etiologic and pathogenetic hypotheses related to chronic inflammatory arthropathies. It is hoped that this project will allow the generation of a robust model to predict disease outcome, which would incorporate a spectrum of early prognostic features, including clinical disease patterns, immunogenetics, and pathologic variables. This model should prove invaluable to clinicians who are attempting to stratify patients for therapeutic strategies, early in their disease course.